Acquired immunodeficiency syndrome (AIDS), characterized by the destruction of the immune system, particularly of CD4 T-cells and susceptibility to opportunistic infections, and its precursor AIDS-related complex (“ARC”), are the result of infection by the HIV (human immunodeficiency) retrovirus. HIV strains include HIV type 1 (HIV-1) and HIV type 2 (HIV type 2). Retrovirus replication involves post-translation processing of precursor polypeptides by a virally encoded protease to produce mature viral proteins, viral assembly and the generation of infective virus. Inactivation of the viral protease (HIV protease) can result in the production of non-infectious virus. Inhibition of HIV protease provides a method for treatment of AIDS and ARC as well as providing a method for treating or preventing HIV infection.
Several HIV protease inhibitors are presently approved for clinical use in the treatment of AIDS and HIV infection, including indinavir (see U.S. Pat. No. 5,413,999), saquinavir (U.S. Pat. No. 5,196,438), ritonavir (U.S. Pat. No. 5,484,801), nelfinnavir (U.S. Pat. No. 5,484,926), lopinavir (U.S. Pat. No. 5,914,332), atazanavir (U.S. Pat. No. 5,849,911), amprenavir (U.S. Pat. No. 5,585,397), darunavir (U.S. Pat. No. 6,248,775) and tipranavir (U.S. Pat. No. 5,852,195). Tipranavir is a non-peptide protease inhibitor, the other listed protease inhibitor are peptide-derived protease inhibitors. Protease inhibitors are currently administered in combination with at least one and typically at least two other HIV antiviral agents, for example, nucleoside reverse transcriptase inhibitors such as zidovudine (AZT) and lamivudine (3TC) and/or non-nucleoside reverse transcriptase inhibitors, such as efavirenz and nevirapine. Combinations of the HIV protease inhibitors may be administered together, such as the combination of lopinavir and ritonavir. Ritonavir can be administered with other HIV protease inhibitors as a booster. Fosamprenavir (fosamprenavir calcium), is a pro-drug of the HIV protease inhibitor and antiretroviral drug amprenavir. Each of the above-listed U.S. patents is incorporated by reference herein in its entirety, for description of methods of treatment and prevention of AIDs and HIV infection employing HIV protease inhibitors, dosage forms for such treatment, drug combinations with HIV protease inhibitors for such treatment, and administration of HIV protease inhibitors alone or in combinations with other antiretroviral drugs.
Of the listed approved HIV protease inhibitors amprenavir, fosamprenavir, darunavir and tipranavir contain sulfonamide structures. Additional HIV protease inhibitors include β-amino acid hydroxyethylamino sulfonamides, α-amino and β-amino acid hydroxyethylamino sulfonamides, lysine sulfonamides, among others. The present invention relates to new sulfonamide derivatives which exhibit HIV protease inhibition, antiretroviral activity and which are useful for the treatment of AIDS and HIV infection.
The following patent documents provide description of HIV protease inhibitors having sulfonamide groups:
U.S. Pat. Nos. 5,585,397; 5,585,397; 5,744,481; 5,786,483; 5,843,946; 5,852,195; 5,852,195; 5,856,353; 5,968,942; 6,060,476; 6,169,181; 6,248,775; 6,248,775; 6,372,778; 6,417,387; 6,436,989; 6,472,407; 6,500,832; 6,646,010; 6,924,286; 7,608,632; 7,981,929; or U.S. published application 20100093811. Each of these patents or published applications describe structures of HIV protease inhibitors and prodrugs thereof which contain at least on sulfonamide group (—NR—SO2—Ar/Het) where the aryl of heteroaryl group can be replaced generally with a boronated aryl group, a boronated heteroaryl group, an aryl group having a protected boronate group, or a heteroaryl group having a protected boronate group. More specifically, the aryl or heteroaryl groups of such HIV protease inhibitor sulfonamides can be replaced with a phenylboronate group, a benzoxaborole group, a borono-pyridyl group or derivative groups thereof where the boronate is protected as described in the present invention. Each of these patents is incorporated by reference herein in its entirety such description of the structures of HIV protease inhibitors and prodrugs thereof and of methods of preparation of such compounds and use of such compounds.
The use of HIV protease inhibitors has been impeded by difficulties with formulation (e.g., poor aqueous solubility), extensive metabolism, adverse effects in some patients, and the development of resistance to protease inhibitors. There is in general a need for new HIV proteases with improved properties for formulation, increased in vivo half-life and to overcome resistance. Additionally, there is a need in the art for HIV protease inhibitors exhibiting enhanced levels of inhibition which will provide for lower effective dosage amounts.